Exposure to high radiation doses causes a well characterized set of radiation dose-dependent and time-dependent organ malfunctions (Acute Radiation Syndrome or ARS), which can lead to severe morbidity and death. Different tissues differ in their sensitivities to radiation exposure, primarily due to differences in the number and turnover of stem cells within each tissue. Bone marrow is one of the most radiation-sensitive tissues, and one of the first signs of acute radiation exposure is bone marrow aplasia. Patients exposed to acute, high dose radiation typically develop severe neutropenia, anemia, thrombocytopenia and lymphopenia within 2-3 weeks of exposure, and many patients die from hematopoietic failure. Patients that survive the early hematopoietic complications of acute radiation exposure may develop gastrointestinal and lung problems over the ensuing months and years. Patients may be exposed to high radiation doses in a hospital setting as a means of treating disease, e.g., cancer, as a result of detonation of a nuclear device, or leakage of radioactivity from a facility containing radioactive substances, e.g., a nuclear power plant. Complications of radiation exposure often limit the amount of radiation treatment cancer patients receive, which reduces effectiveness of the radiation treatment and reduces overall patient survival.
Hematopoietic growth factors have been shown to increase the survival of myelosuppressed animals, because they counteract the complications that result from neutropenia and thrombocytopenia, such as hemorrhages and infections. However, most hematopoietic growth factors are unable to protect animals from lethal doses of radiation (Van der Meeren, 2002). Many hematopoietic factors (proteins that stimulate growth, proliferation and differentiation of blood cells and bone marrow cells) are members of the growth hormone (GH) supergene family of proteins (Bazan (1990); Mott and Campbell (1995); Silvennoinen and Ihle (1996); Blumberg et al. (2001)), which include the following proteins: growth hormone, prolactin, placental lactogen, erythropoietin (EPO), thrombopoietin (TPO), interleukin-2 (IL-2), IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-11, IL-12 (p35 subunit), IL-13, IL-15, IL-19, IL-20, IL-21, MDA-7, IL-TIF, AK-155, oncostatin M, ciliary neurotrophic factor, leukemia inhibitory factor, alpha interferon, beta interferon, gamma interferon, omega interferon, tau interferon, granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), macrophage colony stimulating factor (M-CSF) and cardiotrophin-1 (CT-1) (“the GH supergene family”). It is anticipated that additional members of this gene family will be identified in the future through gene cloning and sequencing. Members of the GH supergene family have similar secondary and tertiary structures, despite the fact that they generally have limited amino acid or DNA sequence identity. The shared structural features allow new members of the gene family to be readily identified.
Recombinant granulocyte colony-stimulating factor (G-CSF) is a 19 kDa protein that stimulates proliferation and differentiation of bone marrow cells into granulocytes (neutrophils, eosinophils and basophils). Recombinant G-CSF has been used to ameliorate neutropenia following myelosuppressive chemotherapy (Glaspy, 2003) and has also been used to accelerate hematopoietic recovery following bone marrow transplantation and to mobilize blood progenitor cells for transplantation (Glaspy, 2003). Recombinant G-CSF has a short half-life in humans and typically is administered by daily injection for 15-21 days following chemotherapy. The requirement for daily administration limits the attractiveness of G-CSF to chemotherapy patients and for the treatment of patients that have been exposed to radiation, such as ARS patients. Although useful doses and dosing regimens of G-CSF for treating chemotherapy-related neutropenia are known, it is not known however if such treatments with G-CSF also provide therapeutic benefits e.g., improved survival and hematopoietic recovery, to patients that have been exposed to radiation, such as ARS patients.
Recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) is a 14 kDa cytokine that regulates proliferation, differentiation and functional activities of a variety of hematopoietic cells of the granulocyte and macrophage lineages, including neutrophils, eosinophils, basophils, monocytes, macrophages, and dendritic cells. Recombinant human GM-CSF is used in a variety of hematopoietic disorders, including reducing the severity of chemotherapy-induced neutropenia, accelerating hematopoietic recovery following bone marrow transplantation and mobilizing blood progenitor cells for transplantation. Recombinant GM-CSF has a short half-life in humans and typically is administered by daily injection for 15-21 days following chemotherapy. The requirement for daily administration also limits the attractiveness of GM-CSF to chemotherapy patients and for the treatment of patients that have been exposed to radiation, such as ARS patients.
Recombinant interleukin-11 (IL-11) is a 19 kDa cytokine that stimulates the proliferation and differentiation of megakaryocytes into platelets (Yang, 1995; Goldman 1995). Recombinant IL-11 is used to ameliorate thrombocytopenia following myelosuppressive chemotherapy in cancer patients (Sitaraman and Gewirtz, 2001). IL-11 administration results in higher platelet nadirs and accelerates platelet recovery in cancer patients receiving chemotherapy. IL-11 has a short half-life in humans and requires daily administration for maximum effectiveness. IL-11 typically is administered to cancer patients by daily injection for 14-21 days following chemotherapy to ameliorate thrombocytopenia. The requirement for daily administration limits the attractiveness of IL-11 to chemotherapy patients and for the treatment of patients that have been exposed to radiation, such as ARS patients.
Growth Hormone (GH) is a 22 kDa protein that may prove useful for treating ARS. Bone marrow stem cells and intestinal cells express receptors for GH and preclinical and clinical studies have shown that GH treatment stimulates expansion and recovery of hematopoietic cells following chemotherapy (Zhang et al., 2008; Sirohi et al., 2007; Carlo-Stella et al., 2004), synergizes with G-CSF to mobilize CD34+ hematopoietic cells in patients who respond poorly to G-CSF alone, and protects intestinal cells from cell death following radiation exposure (Raguso et al., 2002; Howarth, 2003; Howarth et al., 1997; Mylonas et al., 2000; Ersoy et al., 2009).
Whether treatment with a hematopoietic factor protein, such as a long-acting recombinant G-CSF, GM-CSF, GH, or IL-11 can provide a therapeutic benefit such as accelerated hematopoietic recovery or survival benefit to subjects that have been exposed to radiation, such as ARS patients, is not known.